TREAT€3.
1220
1 CONTRIHCTION
FROM THE
“01. 65
JOHNSON
DEPARTMENT OF C H B M I S T R I . ,
\’ALE L’NIVERSITY]
The Reaction of Hydrochloric Acid with 6-Methyl-5,5-dichloroxyhydrouraci11 BY TREAT B. JOHN SON^ Robert Behrend,R in his early classical re- uracil color test. The two pyrimidines I V and searches on the chemistry of 6-methyluracil I, 1 7 are equally sensitive to the action of barium investigated the behavior of this pyrimidine when hydroxide. exposed to the action of bromine and chlorine in While the two hydrouracil derivatives IV and the presence of water. It was found to undeigo 1. exhibit a close similarity in their chemical bepractically a quantitative conversion into the havior) it has been the experience of the author hexahydro pyrimidine derivatives, viz., 6-methyl- that the 4methylhydrouracils I1 and I11 differ 5,.5-dibromoxy- and 6-methyl-5,5-dichloroxyhy-decidedly in their relative reactivity under comdrouracils expressed by the formulas I1 and 111, parable experimental conditions. Behrend3 was conscious of this fact and states in his early respectively. paper that the bromine cornpound I1 is easily NH-CO NH-CO decomposed by warming with alcohol giving 5! 1 Br? + H20 ’ C1, Hz0 CO CBr? 6CO CH bromo-6-methyluracil, while the corresponding ’ ll ! ; NH-COH XH-CCHa chlorine compound I11 is not altered by this , treatment and can be recrystallized repeatedly CHs from alcohol without change. He also found I1 I NH-CO that the bromine compound I1 is easily converted 1 1 co CCl? to 5-bromo-6-methyluracil by warming with 1 1 water, while the chlorine compound 111 can be NH--COH exposed to long digestion at 100” without alteraCH3 tion. I11 Behrend extended his experimental study of 6We now recognize this change brought about methyl-5,5-dichloroxyhydrouracilI11 by heating by the action of halogens as characteristic of it with alcohol and also water over a temperature representatives of the true uracil type; and the range of 140 to 150”)but without the formation of study of such hydrouracil compounds still prom- the expected 6-methyl-5-chloruracil in either case. ises to yield results of special interest during Alcoholysis or hydrolysis led to the formation of the progress of pyrimidine research in this ammonia and other difficultly soluble products Laboratory. The pyrimidine IV prepared by which were not So far as the author the action of bromine on uracil is the key re- is aware, no explanation) to date, has been given agent serving as the basis of the specific color of the nature of these hydrolytic changes. The test for this pyrimidine and cytosine.4 It is author’s interest in the chemistry of this class important to note here that the corresponding of pyrimidines has induced him to undertake a chlorine compound V) first synthesized by the comparative study of the reactivity of the two authorl5 can be substituted for the bromine coni- pyrimidines I1 and 111, and a report is now renpound I V for the successful application of this dered on the chemical deportment of both compounds when exposed to the action of strong NH-CO NH---CO I I hydrochloric acid.7 $0 L C L CO CBr: The author now finds that the two 4-methylI 1 : i NH-CHOH KH-CHOH hydrouracils I1 and I11 differ decidedly in their IV v behavior toward hydrochloric acid. The bro(1) Researches on Pyrimidines, CLXXIX. mine compound I1 reacts to undergo the normal (2) The author expresses here his acknowledgment of the assistance change expected yielding a true uracil derivative, given by Mr. C. 0. Edens in the performance of analytical work re-
+
____f
ported in this paper. (3) R. Behrend, Awn., 229, 18 (1885); 256, 57 (1886);List, 2S6, 22 ( 1886). (4) “Color Test for Uracil,” by Wheeler and Johnson, -7. Biol. ( h r m , 3, 183 (1007). (.i) J < > h n \ o n ., l m ( t ! r j r ) J , 40, I!) I l ! l O X )
(6) Behrend, A m , 936, 61 (1886). Qztotatton. “Unter Bildung von 4mmoniak und anderen zum the11 schaer Ibslichen, noch nicht ndher untersuchten I’roducten” “doch wird kein Chlormethyluracil gebildet.” ( 7 ) Behrenti’q euperirnent~ w i t h d ~ o h o l md N t t l r 11 140 1 -)Oo =ill / I C r t j x t t i d I I ti 1 )
June, 1943 REACTION OF HYDROCHLORIC ACIDWITH 6-METHYL-5,5-DICHLOROXYHYDROURACIL 1221
viz., 6-methyl-5-bromouracil.
The chlorine compound 111, on the other hand, reacts with hydrochloric acid without formation of 6-rnethyl-5chlorouracil, but is transformed almost quantitatively into a new compound of unknown structure and having the empirical formula C10Hs06N4C12. This same substance is also formed by digesting the chlorine compound I11 with acetic anhydride. The reaction is expressed in the equation below. 2CrHsOaNzClz
Jr CioHsOsNiClz + HzO + 2HC1
The composition of the new compound indicates that the 4-methylhydrouracil I11 first undergoes a condensation with eliniination of one mole of water with formation of an heterocyclic ether construction VI, analogous to the production of a,a'-dimethyl-P,P'-furan-dicarboxylicacid by the action of hydrochloric acid on y-diacetosuccinic acid.s The further loss of two molecules of hydrochloric acid from such an heterocyclic ether V I would account for the subsequent formation of a compound represented by the empirical formula CloHs06N4C12. That we are dealing here with a dimolecular condensation product, as expressed by this formula, is confirmed by the analytical values obtained for its molecular weight (339 and 341). NH-CO
I I co CCl2 I 1 NH-C--O I
NH-CO
'
I
CO/$!H
'/
1
I
CO-NH
1
CHs
To represent the constitution of this new compound we have tentatively assigned to it the structural formula VII. This is a representative of an entirely new type of pyrimidine compound, and, if correctly interpreted, i t is the first pyrimidine to be described in the literature possessing the cyclic structure of the unknown 6-methyl-1,5bicyclouracil VIII. The pyrimidine ether VI1 is soluble in alkali and is reprecipitated unchanged by addition of acids. (8) Knorr, Bru., 22, 166, 172 (1889); 47, 1137 (1894); Harrow, A ~ G .801, , 137 (1880).
I
YH /I
NH-CCHs I
Experimental Part The Oxide or Ether of dMethyl-6-oxy-S-chloro-1,5bicyclouracil, M.-This bicyclouracil derivative, which is an ether formation of the hypothetical 1,5-bicyclouraci1 compound, is obtained in excellent yield by dissolving 6methyl-5,5-dichloroxyhydrouracil I11 in strong hydrochloric acid, and boiling the resulting solution for one or more hours. Many hydrolysis experiments have been conducted successfully by the author using proportions of 2 g. of the pyrimidine I11 dissolved in 20,25,40 and 50 cc. of concentrated hydrochloric acid. Variable periods of digestion have been applied, uiz., from one t o fifteen hours. The reaction, however, is practically complete within one and one-half hours, and the fact that the yield is little diminished by long digestion indicates the strong resistance of the substance t o further hydrolytic change. The bicycle compound deposits slowly from the boiling solution, and on cooling a t the end of the reaction period separates in the form of flat prisms. It is purified easily by crystallization from hot water or acetic acid, and the yield produced from 2 g. of the pyrimidine I11 averages 1.2 to 1.7 g. melting from 266-270' with decomposition. The purified product melts at 270-275" with decomposition. The ether dissolves in alkali without alteration and is reprecipitated by acids. Analysis after drying to constant weight at 100-110' gave C
I I clzc co -2HC1 I l C-NH
I
I
Z C O
N-bHCH3 VI11
CO-NH
CHa (CicJUA"C1z) VI1
NH-CO
Calcd. for ChH602N2Cl: Calcd. for CloHs06N4C12 (VII) : Found : Foutid: Found : Found : Found :
H
37.38 3.11 35.80 35.50 35.51 35.60
N
CI
17.44 22.11
2 . 4 0 16.71 21.18 2.60 16.51 21.07 2 . 5 5 16.40 21.06 2.70 16.44 21.10 16.61 16.48
Molecular Weight Determination by the Ebullioscopic Method.-Conducted with anhydrous methanol in Menzies and Wright a p p a r a t u ~ . ~ Anal. Calcd. for ClOHsObN4Cl:: mol. wt., 335. Found: mol. wt., 339 and 341. This same compound VI1 was also formed as follows. One gram of 6-methyl-5,5-dichloroxyhydrouracil I11 was dissolved in 10 cc. of acetic anhydride and the solution refluxed a t its boiling point for one hour. After cooling, the insoluble reaction product was separated and purified by crystallization from hot water. It melted a t 270-275" with effervescence. Anal. Calcd. for CioHs06NaClz: N, 16.71. Found: N, 16.65, 16.70. Experiments with 6-Methyl-S,5-dibromoxyhydrouracil I1 Action of Hydrochloric Acid.-Digestion of 2 g. of this pyrimidine I1 with 30 cc. of concd. hydrochloric acid led to iiriniediate destruction of the pyrimidine with evolution (9) Menzies and Wright, THIS JOURNAL, I S , 2309 (1921).
1222
WILLIAM F. KINGKAND ELIASEPSTEIN
of nascent bromine. After refluxing until all free bromine was expelled the insoluble reaction product was separated and recrystallized from hot water. It melted with decomposition at 260-261 ' and was identitied as 6-methyl-5bromouracil. The yield was quantitative. Anal. Calcd. for CbHb02NzBr: C, 29.26; H, 2.63; N, 13.65. Found: C, 29.26; H, 2.43; N, 13.88. This same decomposition was accomplished by boiling a solution of the pyrimidine I1 in acetic anhydride. The yield was quantitative. Behavior of the Ether VII on Reduction 1. Action of Tin Chloride and Hydrochloric Acid.-One half a gram of the bicyclouracil compound VI1 was digested a t 100" in 15 cc. of dilute hydrochloric acid with 2 g. of stannous chloride for six hours. The mixture was then allowed to cool when colorless crystalline material deposited. This was identified as a mixture of 6-methyl-5chlorouracil and the unreduced bicyclo compound VII. The difference in water solubility permitted easy separation and the 6-methyl-5-chlorouil was obtained in the form of prisms which did not melt below 300". The recovered bicyclo compound VI1 crystallized from boiling water and melted a t 270-2i5' with decomposition. Anal. Calcd. for CloHsObNrClz: N, 16.71. Pound: X , 16.74, 16.69. 2. Action of Hydriodic Acid.-One gram of the bicyclo compound VII, melting a t 270-27BO was boiled for fifteen minutes with 10 cc. of hydriodic acid of sp. gr. 1.5 and an excess of red phosphorus. The resulting solution was then diluted with 30 m. of water and filtered while hot. A colorless solution resulted which deposited a small amount of crystals that were filtered off and identitied as 6-methyl-5chlorouracil. The acid filtrate was concentrated by evapo-
VOl. 65
ration a t 100" to a small volume and cooled wheu 6methyluracil I separated. This was purified by crystallization from hot water and did not melt below 300'. It was free from chlorine. ..lad. Calcd. for C~HBOZNZ: C, 47.63; H, 4.76; N, 22.22. Found: C, 47.62; H, 4.66; N, 22.33. Action of Ammonia on 6-Methyl-5-dichloroxyhydrouracil 111.-Two grams of this pyrimidine was dissolved in 50 cc. of concentrated aqueous ammonia and the solution preserved a t ordinary temperature in a stoppered bottle. After standing one week the solution was evaporated at 100" to expel the excess of ammonia and the filtrate cooled. Pure 6-methyl-5-chlorouracil separated and was the only product identified, and did not melt below 300". We obtained no evidence of the formation of the bicyclo compound VII.
Summary 1. 6-Methyl-5,5-dichloroxyhydrouracilI11 is converted by the action of hydrochloric acid into a dichloro ether derivative of the hypothetical 6-methyl-6-oxy-l,5-bicyclouracil VII. 2. The corresponding B-methyl-5,5-dibromoxyhydrouracil I1 is transformed by action of hydrochloric acid into G-methyl-5-bromouracil. No evidence of the formation of a bicyclouracil derivative was obtained. 3. These same respective changes can also be brought about by the action of acetic anhydride. NHWHAVEN, CONNECTICUTRECEIVED MARCH11, 1943
[CONTRIBUTION FROM RESEARCH LABORATORIES O F NOCOCOL CHEMICAL M F G .
CO., I N C . ]
Preparation of Aminobenzoic Acid Esters of Substituted Monoalkyl Amino Alcohols.
I1 BY WILLIAM F. RINGK'AND ELIASEPSTEIN In a previous paper,la the author described the Table I gives the physical constants of the amino amino benzoates of P-alkylamino-a,a-dimethyl-alcohols and the molecular refractions. The amino alcohols were condensed with p ethanols where the alkyl group contained from 1 nitrobenzoyl chloride in an aqueous alkaline to 3 carbon atoms. This paper deals with members of the same medium as described in our previous paper. The series in which the nitrogen alkyl group contains nitro esters are all yellow solids which give posi6 to 8 carbon atoms which were made for com- tive nitroso tests. parison with members of another series. TABLE Ia In general, the amino alcohols were prepared ~-ALKYLAMINOa,a-DIMETHnETHANOLS as previously described, with the following ex[R " C H & ( CHs)zOH] ceptions: the solvent used was 50% isopropanol Alkyl B. P., MR, MR, grou P OC. dWm n% calcd. found Diff. solution and the mixtures were refluxed for about 224-228 0.8618 1.4406 53.35 53.05 - 0 . 3 0 sixty hours. The yields were approximately 45y0. n-Hexyl n-Heptyl 242-246 ,8567 1.4424 57.95 57.85 - . l o (1) Present address: Benzol Products Company, Newark, N. J la) Goldberg, Ringkand Spoerri, THIS J U U R N A L , 61, 3362 (1939)
Octyl-2 2-Ethylhexyl
245-248 245-248
,8560 ,8860
1,4410 61.56 62.09 1.4436 61.56 6 2 . 4 2
-
.53 .86
